Whereas the importance of plasma lipoprotein(a) [Lp(a)] levels as a risk factor for premature coronary artery disease (CAD) is certain, it is not clear if the apolipoprotein(a) [apo(a)] phenotype plays an additional and independent role. To investigate the possible effect of apo(a) phenotype on premature CAD (in patients < 55 years of age), plasma Lp(a) concentrations, the apo(a) phenotypes, and their relation with many recognized CAD risk factors were examined in 96 non-diabetic male patients with angiographically defined CAD and in 83 age-matched male control subjects with no angiographic evidence of CAD. Results demonstrate that patients with premature CAD are characterized by higher Lp(a) levels (24 +/- 21 vs 17 +/- 15 mg/dl, p < 0.01) and a higher frequency of S2 phenotype (32% vs 15%, p < 0.01). Patients with an S2 phenotype exhibited significantly higher plasma Lp(a) concentrations than control subjects with the same isoform (37 +/- 22 vs 22 +/- 17 mg/dl, p < 0.05). A significant correlation was found between apo B and Lp(a) levels in patients with an S2 phenotype. In addition, patients had a low frequency of S1 and S4, and a high frequency of double-band phenotypes of apo(a). Multivariate analysis did not demonstrate an independent role for apo(a) phenotype as a risk factor for premature CAD. In conclusion, CAD patients < 55 years of age have a very different pattern of apo(a) phenotypes than subjects with no angiographic evidence of CAD; this study confirms the hypothesis that apo(a) phenotype may play an additional role in the etiology of premature CAD.